In collaboration with several Principal Investigators at the CCR/NCI, in silico screening of large small-molecule databases are being conducted for a number of molecular targets relevant for cancer. We are using the (http://ccr.cancer.gov/staff/staff.asp?profileid=6282) CADD Group's resources, including our screening (http://ccrintra.cancer.gov/cms/annual_reports/projects/printer_friendly_report.asp?ProjID=6864) databases to generate lists of compounds to be purchased from (http://www.chemnavigator.com/nih.asp) commercial suppliers with the goal of obtaining novel lead compounds in in vitro and/or cell-based assays. Currently, we are predominantly working on the targets Akt (PH domain), in collaboration with Phillip Dennis, Cancer Therapeutics Branch, CCR, NCI; c-Met, in collaboration with Donald Bottaro, Urologic Oncology Branch, CCR, NCI, and Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI; HSP90, in collaboration with Len Neckers, Cell & Cancer Biology Branch, CCR, NCI; polo-Box domain of polo-like kinase 1, in collaboration with Kyung S. Lee, Laboratory of Metabolism, CCR, NCI; Grb2 SH2 domain, in collaboration with Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI; PKC, in collaboration with Peter Blumberg, Laboratory of Cancer Biology and Genetics, CCR, NCI, and Victor E. Marquez, Laboratory of Medicinal Chemistry, CCR, NCI; herpes thymidine kinase, in collaboration with Victor E. Marquez, Laboratory of Medicinal Chemistry, CCR, NCI; tyrosyl-DNA phosphodiesterase (Tdp1), in collaboration with Yves Pommier, Laboratory of Molecular Pharmacology, CCR, NCI; bis-imidazoacridone DNA intercalators, in collaboration with Sergey Tarasov, Structural Biophysics Laboratory, CCR, NCI; small-molecule mimetics of a surface patch of thrombospondin-1 (TSP1) interacting with CD47, in collaboration with David D. Roberts, Laboratory of Pathology, CCR, NCI; the interaction of the transcription factor HIF-1 alpha with cofactor p300, in collaboration with William Douglas Figg Sr., Medical Oncology Branch, CCR, NCI; and the aberrant chimeric transcription factor ASPL-TFE3, in collaboration with Robert H. Shoemaker, Screening Technologies Branch, DTP, DCTD, NCI. For Akt, c-Met, the polo-Box domain of plk1, and Tdp1, initial hit sets have been generated, screening samples purchased, and these samples assayed by our collaborators. Inhibitory activity was found for a number of samples in each one of these assay. Sample sets have been proposed for purchase in the TSP1/CD47 and HSP90 projects.